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A Possible Zebrafish Model of Polycystic Kidney Disease: Knockdown of wnt5a Causes Cysts in Zebrafish Kidneys
Published on: December 2, 2014
Cardiovascular, skeletal, and renal defects in mice with a targeted disruption of the Pkd1 gene
1Department of Genetics, University of Cambridge, Cambridge CB2 1TN, United Kingdom.
Insights
Autosomal dominant polycystic kidney disease (ADPKD) results from mutations in PKD1 or PKD2. New mouse models reveal Pkd1
Area of Science:
- Genetics and Molecular Biology
- Developmental Biology
- Cardiovascular Research
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by cyst formation in multiple organs.
- Mutations in PKD1 and PKD2 genes, encoding polycystins, are the primary cause of ADPKD.
- Previous studies in mouse models showed varying phenotypes, including renal cysts and cardiac defects, depending on the specific gene mutation.
Purpose of the Study:
- To investigate the role of polycystin-1 (P பாதிக்கிறது1) in cardiovascular development and organogenesis using a novel mouse model.
- To define the expression pattern of Pkd1 during embryonic development.
- To explore potential novel functions of polycystin-1 in relation to ADPKD pathogenesis.
Main Methods:
- Generation of a targeted mutation in Pkd1 (Pkd1(del17-21betageo)) utilizing a lacZ reporter gene to track Pkd1 expression.
- Analysis of Pkd1(del17-21betageo) +/- and -/- mice for phenotypic abnormalities, including cystogenesis and cardiovascular development.
- Histological examination of embryonic tissues to identify developmental defects.
Main Results:
- Pkd1(del17-21betageo) +/- adult mice developed renal and hepatic cysts, consistent with ADPKD.
- Pkd1(del17-21betageo) -/- embryos exhibited embryonic lethality due to severe cardiovascular defects, including double outflow right ventricle and myocardial disorganization.
- Pkd1 expression was detected in maturing tubular epithelial cells during nephrogenesis, coinciding with the onset of cyst formation in other ADPKD models.
Conclusions:
- Polycystin-1 plays a critical role in embryonic cardiovascular development and skeletal formation.
- The expression pattern of Pkd1 during nephrogenesis supports its involvement in tubule development and cystogenesis.
- These findings reinforce the hypothesis of in vivo interaction between polycystin-1 and polycystin-2, where their dysfunction leads to ADPKD-related abnormalities.
Abstract:
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by cyst formation in the kidney, liver, and pancreas and is associated often with cardiovascular abnormalities such as hypertension, mitral valve prolapse, and intracranial aneurysms. It is caused by mutations in PKD1 or PKD2, encoding polycystin-1 and -2, which together form a cell surface nonselective cation ion channel. Pkd2-/- mice have cysts in the kidney and pancreas and defects in cardiac septation, whereas Pkd1(del34) -/- and Pkd1(L) -/- mice have cysts but no cardiac abnormalities, although vascular fragility was reported in the latter. Here we describe mice carrying a targeted mutation in Pkd1 (Pkd1(del17-21betageo)), which defines its expression pattern by using a lacZ reporter gene and may identify novel functions for polycystin-1. Although Pkd1(del17-21betageo) +/- adult mice develop renal and hepatic cysts, Pkd1(del17-21betageo) -/- embryos die at embryonic days 13.5-14.5 from a primary cardiovascular defect that includes double outflow right ventricle, disorganized myocardium, and abnormal atrio-ventricular septation. Skeletal development is also severely compromised. These abnormalities correlate with the major sites of Pkd1 expression. During nephrogenesis, Pkd1 is expressed in maturing tubular epithelial cells from embryonic day 15.5. This expression coincides with the onset of cyst formation in Pkd1(del34) -/-, Pkd1(L) -/-, and Pkd2-/- mice, supporting the hypothesis that polycystin-1 and polycystin-2 interact in vivo and that their failure to do so leads to abnormalities in tubule morphology and function.
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